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Immunological Challenges of Regenerative Therapies –What, Why, How ?
Hans-Dieter Volk
Institute of Medical Immunology&
BIH Center for Regenerative Therapies (BCRT)&
Dept. Immunology, Labor Berlin Charité & Vivantes GmbH
Charité – Universitätsmedizin Berlin and Berlin Institute of Health
IMI
Regenerative Therapies are more than Stem Cell therapies
Regenerative Therapies are more than Stem Cell therapies
Regenerative Therapies are more than Stem Cell therapies
Regenerative Therapies are more than Stem Cell therapies
Inflammation/Immunity – a major common challenge
Goal: to support endogenous regeneration and
to improve engraftment and function of biological replacement strategies
Goal: to support endogenous regeneration and
to improve engraftment and function of biological replacement strategies
Challenges: “Aged” immune system, Immunogenicity of Therapeutics, Reshaping Immune Response
Inflammation/Immunity – a major common challenge
Goal: to support endogenous regeneration and
to improve engraftment and function of biological replacement strategies
Challenges: “Aged” immune system, Immunogenicity of Therapeutics, Reshaping Immune Response
Inflammation/Immunity – a major common challenge
Intratissue immunity = part of dynamic tissue homeostasis
immune cells
parenchymalcells
ECM
Tissue
stromal cells
immune cells
parenchymalcells
ECM
Tissue
Challenges (e.g. trauma, infection, (auto)immune attack…)
Recruitmentof cells
stromal cells
Challenged tissue homeostasis triggers recruitment of cells
Immune „Aging“ Naive / early memory T cells Effector T cells
Repetitive antigen(pathogen) challenge
infiltration/inflammation infiltration/inflammation(+) +++
immune cells
parenchymalcells
ECM
Tissue
Challenges
Recruitmentof cells
stromal cells
Enhanced tissue infiltration / inflammation by effector T cells
Immune „Aging“ Naive / early memory T cells Effector T cells
Repetitive antigen(pathogen) challenge
immune cells
parenchymalcells
ECM
Tissue
Challenges
Recruitmentof cells
stromal cells
SPF housing
SPF housing preserves naive immune system despite aging
infiltration/inflammation infiltration/inflammation(+) +++
Immune „Aging“ Naive / early memory T cells Effector T cells
Repetitive antigen(pathogen) challenge
immune cells
parenchymalcells
ECM
Tissue
Challenges
Recruitmentof cells
stromal cells
SPF housingNon-SPF housing
infiltration/inflammation infiltration/inflammation(+) +++
Non-SPF housing brings murine system close to human ones
Age
Frequency of effector T cells in spleen / blood
18 moSPF3 mo
SPF
Non-SPF housing brings murine system close to human ones
Japp A Cytometry 2017, Reinke S Sci Transl Med 2013, Schmidt-Bleek et al. Front Immunol 2017, Sbierski-Kind et al. Front Immunol 2018, Schlundt Front Immunol 2019
Enhanced and decreased level of Teff and Tnaive CD8+ (similar for CD4+, B-Ly, myeloid), respectively, in mice from pet shop (PS) vs. quarantine (Qua) vs. non-SPF vs. SPF housing.
Multiparameter (40) CyTOF analysis
Age
Frequency of effector T cells in spleen / blood
18 moSPF3 mo
SPF
Non-SPF housing brings murine system close to human ones
Japp A Cytometry 2017, Reinke S Sci Transl Med 2013, Schmidt-Bleek et al. Front Immunol 2017, Sbierski-Kind et al. Front Immunol 2018, Schlundt Front Immunol 2019
Enhanced and decreased level of Teff and Tnaive CD8+ (similar for CD4+, B-Ly, myeloid), respectively, in mice from pet shop (PS) vs. quarantine (Qua) vs. non-SPF vs. SPF housing.
Multiparameter (40) CyTOF analysis
Age
Frequency of effector T cells in spleen / blood
18 moSPF3 mo
SPF
3 monon-SPF
12 monon-SPF
Non-SPF housing brings murine system close to human ones
Japp A Cytometry 2017, Reinke S Sci Transl Med 2013, Schmidt-Bleek et al. Front Immunol 2017, Sbierski-Kind et al. Front Immunol 2018, Schlundt Front Immunol 2019
18 monon-SPF
Tnaive and Tmemory/effector cell counts
Japp A Cytometry 2017, Reinke S Sci Transl Med 2013, Schmidt-Bleek et al. Front Immunol 2017, Sbierski-Kind et al. Front Immunol 2018, Schlundt Front Immunol 2019
Fast Test of ImmunoAge - Flowcytometry
Age
Frequency of effector T cells in spleen / blood
18 moSPF3 mo
SPF
3 monon-SPF
12 monon-SPF
Non-SPF housing brings murine system close to human ones
20-50 µl
Non-SPF
SPF
18 monon-SPF
Age
Frequency of effector T cells in spleen / blood
18 moSPF3 mo
SPF
3 monon-SPF
12 monon-SPF
ImmunoAging has a strong impact on thecourse of distinct disease models:
- Organ Transplantation- Spontaneous abortions
- Bone fracture healing- Acute muscle injury- Type 2 Diabetes- Acute Ischemia/Reperfusion Injury- …
- Gene therapy
Non-SPF housing brings murine system close to human ones
Japp A Cytometry 2017, Reinke S Sci Transl Med 2013, Schmidt-Bleek et al. Front Immunol 2017, Sbierski-Kind et al. Front Immunol 2018, Schlundt Front Immunol 2019
Katharina Schmidt-Bleek
Simon Reinke
Christian Bucher
Julia Sbierski-Kind
Sven Geissler
Andreas Thiel
Advanced Preclinical in vitro & in vivo Models
Advanced ModelsClinically relevant
models
Large aimals
Humanized NSG mice& ImmunoAged mice
Biosamples fromdisease-specificpatient population
Multiorgan 3D-chips„Patient-on-the-Chip“
Limited predictive valuefor diseases
Higher predictive valuefor diseases
Conventional preclinical modelsusing mice kept under
SPF housing conditions and biosamples from healthy donors
Goal: to support endogenous regeneration and
to improve engraftment and function of biological replacement strategies
Challenges: “Aged” immune system, Immunogenicity of Therapeutics, Reshaping Immune Response
Inflammation/Immunity – a major common challenge
ImmunoTherapies – innovation drivers in medicine
Restorating ProtectiveImmune Response
Fighting cancer and severe infections
Reshaping UndesiredImmune Response
PreventingSelf-destruction or
Transplant rejection
„Living Drugs“ (ATMP)
Biologicse.g. checkpointinhibitors
e.g. anti-IL-17 mAb
e.g. CAR-T cells
e.g. Treg cells
ImmunoTherapies – innovation drivers in medicine
Restorating ProtectiveImmune Response
Fighting cancer and severe infections
Reshaping UndesiredImmune Response
PreventingSelf-destruction or
Transplant rejection
„Living Drugs“ (ATMP)
Biologicse.g. checkpointinhibitors
e.g. anti-IL-17 mAb
e.g. CAR-T cells
e.g. Treg cells
ReSHAPING undesired immune reactions by regulatory T cells (Treg)
Current strategy:Control of dominant immunopathology bychronic multi-drug treatment
1DG INTERNAL POLICIESWorkshop 2017
Autoimmune Diseases
Solution: Reshape immune balance by Regulatory T cells (Treg)
Treg cells
One Master Cell Product –Many Applications
Aim:ReSHAPEimmune balance
Problem:Increasing prevalence of immune diseases (>10% of chronic diseases), Burden: >100 bn €/a EU1
Current strategy:Control of dominant immunopathology bychronic multi-drug treatment
1DG INTERNAL POLICIESWorkshop 2017
Autoimmune Diseases
Solution: Reshape immune balance by Regulatory T cells (Treg)
Treg cells
One Master Cell Product –Many Applications
Aim:ReSHAPEimmune balance
Problem:Increasing prevalence of immune diseases (>10% of chronic diseases), Burden: >100 bn €/a EU1
ReSHAPING undesired immune reactions by regulatory T cells (Treg)
ReSHAPING undesired immune reactions by regulatory T cells (Treg)
PetraReinkePI OneStudyONE nTreg13
Exemplary Case: My life is better by reshaping immune system
1995 2015 03 / 2015 04/2015 10/2015 2019
ChronicKidneyFailure Dialysis
T1 Diabetes
KidneyTransplan-
tation
Standard of Care
Lifelong Multidrug Therapy(>30 pills/day)
adverse effects, costs, quality of life
Cardio-myopathy
1995 2015 03 / 2015 04/2015 10/2015 2019
ChronicKidneyFailure Dialysis
T1 Diabetes
KidneyTransplan-
tation
Lifelong Multidrug Therapy(>30 pills/day)
adverse effects, costs, quality of life
Cardio-myopathy
RegulatoryT cell
Therapy Minimizing Immunosuppression⇒ 3 pills/d instead >30 pills/d⇒ safe (no infection, no cancer)⇒ excellent graft function (creatinine 1.1)
x Standard of Care
Exemplary Case: My life is better by reshaping immune system
Promising clinical results in LD kidney transplant patients⇒ Safe⇒ hints of efficacy
triple immunosuppression=> FK monotherapy
W1 W24 W60 Y3
Switch to FK monotherapy in the Treg therapy group is feasible(FIH phase I/IIa study)
1st generation of polyclonal Treg – safe and hints of efficacy
Refined Translation – from bed to bench and back to bed next generation regulatory T cell (Treg) approaches
Next-GenerationTreg
Epigenetic and gene editing(CRISPR/Cas)
Gene modified (lentiviral)
Refined Translation – from bed to bench and back to bed next generation regulatory T cell (Treg) approaches
H2020
Next generation T cell products:(M. Schmück-Henneresse / D. Wagner / L. Amini)
Next-generation CRISPR/Cas modified CNI - resistant Treg
Problem: Basal immunosuppression
(tacrolimus) inhibits also Treg
Next generation T cell products:(M. Schmück-Henneresse / D. Wagner / L. Amini)
Effective in vitro expansion and CTLA4 Expressionof KO-TREG under Tacrolimus but inhibition by CSA (safety switch)
Next-generation CRISPR/Cas modified CNI - resistant Treg
Vector-freeCRISPR/Cas9-mediated
FKBP12-KO
d7 of TREG culture
1 2 3 4 5
Tacrolimus-resistant FKBP12–/– TREG
FoxP3
CD25
11.2% 99.1%
High purity sort
Problem: Basal immunosuppression
(tacrolimus) inhibits also Treg
Gundry MC et al.Cell Report 2016
Next generation T cell products:(M. Schmück-Henneresse / D. Wagner / L. Amini)
Effective in vitro expansion and CTLA4 Expressionof KO-TREG under Tacrolimus but inhibition by CSA (safety switch)
Next-generation CRISPR/Cas modified CNI - resistant Treg
Vector-freeCRISPR/Cas9-mediated
FKBP12-KO
d7 of TREG culture
1 2 3 4 5
Tacrolimus-resistant FKBP12–/– TREG
Problem: Basal immunosuppression
(tacrolimus) inhibits also Treg
FoxP3
CD25
11.2% 99.1%
High purity sort
Gundry MC et al.Cell Report 2016
ProTacFIH-Trial2020/1
Goal: to support endogenous regeneration and
to improve engraftment and function of biological replacement strategies
Challenges: “Aged” immune system, Immunogenicity of Therapeutics, Reshaping Immune Response
Inflammation/Immunity – a major common challenge
Problem: Pre-immunity to SpCas9
SpCas9
MHC
TEFF
SpCas9 fragments
Gene-edited CellSpCas9-peptide presentation
Pre-formed SpCas9-reactive Teff cellsregonize CRISPR/Cas edited cell products
⇒ Release of inflammatory cytokines⇒ Killing of gene-edited cells
Problem: Pre-immunity to SpCas9
SpCas9
MHC
TEFF
SpCas9 fragments
Gene-edited CellSpCas9-peptide presentation
Pre-formed SpCas9-reactive Teff cellsregonize CRISPR/Cas edited cell products
⇒ Release of inflammatory cytokines⇒ Killing of gene-edited cells
Test for detecting„fading-out“ Cas peptides
Cas-specifc Treg
Problem solutions
Problem: Pre-immunity to SpCas9
SpCas9
MHC
TEFF
SpCas9-reactive regulatory T cell
TREG
SUPPRESSION
SpCas9 fragments
Gene-edited CellSpCas9-peptide presentation
SpCas9-specific Treg cellsregonize CRISPR/Cas editedcell products andinhibit
⇒ release of inflammatorycytokines
⇒ killing of gene-edited cells
Conclusions for BIH/Charité Translation Strategy
1. SPF housing limits the value of many experimental models as predictive disease models⇒Need for controlled „dirty“ housing at Charité/BIH
2. Reshaping immune responsiveness is a key element to support endogenous regeneration as well asengraftment of tissue replacement approaches that requires in-depth immune biomarker analyses
⇒Need for high-end immune biomarker unit (spin-off CheckImmune)
3. Immune (cell) therapy is one of the most dynamic fields in medicine with high translational potencyat academic centers
⇒Need for developing a Hub (BeCAT + spin-off incubator + biotech/pharma) on AdvancedTherapies at Charité/BIH
Defined, chemically produced Small Molecules
since >120 years
Protein-based drugsproduced in living cells
Biologics
since >30 years since >10 years
chance of cure(game changer)
complexity
“Living” drugs(somatic cells, gene modified cells, in vivo gene therapy, engineered tissues)
Advanced Therapies (ATMP)
Complexity of chronic diseases requires complex therapeutic approaches
The Novel Class of „Living“ Drugs (Advanced Therapies) – a Game Changer
1,069Clinical Trials
underway worldwideby end of Q2 2019
Phase I: 358 Phase II: 617 Phase III: 94
Gene Therapy Gene–modified Somatic Cell TissueCell Therapy Therapy Engineering
366 410 249 44
Alliance Regenerative Medicine Report Q2 2019
Advanced Therapies – not just a dream, it is already “reality“
2019: about a dozen products approved in Europe (marketing authorization)
drug discovery
business models
supply chain
clinical trialdesign
health economy/reimbursement
drugs raw material
scaling-up
pharmacokineticspharmacodynamics
manufacturingmode-of-actionmultiple effects
ethics
complex dataat all TRLs
preclinicalmodels
„Living“ Drugs (AT) – a disruptive innovation shattering current paradigms
§ 91bWissenschaftsrat 2017
Concept ranked as 1st
30 Mio € for the „hardware“GMP-Research Building
Late Clinical Research and Marketing Authorization
Industry PartnershipPharma & Biotech
& Technology Providers
Spin-off of BCRT: Berlin Center for Advanced Therapies (BeCAT)
Prof. Dr.med. Petra Reinke
MoreFasterSuccessfulAffordableAccessible
High need for targeted efforts and a sustainable large-scale research initiative in Europe
Mission:Building-up an ecosystem to
Overcome the technological and regulatory roadblocks for Advanced Therapies in Europe andDeliver a pipeline of dozens of revolutionary Advanced Therapy products by 2030
outgrowingcommercial infancy
Who is behind the RESTORE community ?
Key Elements to support Advanced Therapies in a new way
Infrastructure(Translational Hub´s)
Structured Research and Innovation Actions (RIAs)
Technology Research& Innovation Platforms
Private Public Partnershipand innovative SMEs
Coordination & Support Action(CSA)
Suitable Horizon Europe Programme Elements for RESTORE:- European Regional Development Fund- European Innovation Ecosystems & EIT Health- European Innovation Council (EIC)- RIA´s within Cluster Health- Partnership Innovative Health Initiative- Mission Cancer
Academic, Industry, Patient and Public Society
transparent and dynamic governance
Bilateral interaction with
Regulatory Bodiesat national/EU level
https://restore-horizon.eu
Conclusions for BIH/Charité Translation Strategy
1. SPF housing limits the value of many experimental models as predictive disease models⇒Need for controlled „dirty“ housing at Charité/BIH
2. Reshaping immune responsiveness is a key element to support endogenous regeneration as well asengraftment of tissue replacement approaches that requires in-depth immune biomarker analyses
⇒Need for high-end immune biomarker unit (spin-off CheckImmune)
3. Immune (cell) therapy is one of the most dynamic fields in medicine with high translational potencyat academic centers
⇒Need for developing a Hub (BeCAT + spin-off incubator + biotech/pharma) on AdvancedTherapies at Charité/BIH
4. Immunology is a major common challenge for Regenerative Therapies and a research focus at theBCRT with internationally recognized USP
⇒Need for adequate appointment policy
GMPPetra ReinkeSybill Landwehr KenzelDaniel KaiserAndy RoemhildCarola Beier Henrike Führer Anne ForkeInsa Lehmann …
Biomarker & PreclinicsBirgit SawitzkiNina BabelMichael Schmueck-HenneresseDimitrios WagnerLeila Amini, Ghazaleh ZarrinradDesiree Jaqueline WenderingMathias Streitz, Kerstin Jülke,Gerald Grütz, Levent AkyüzChristian Meisel + LB Immunology Team
Clinical Trial(s)Petra ReinkeMohamed Abou El-EneinSybill Landwehr-KenzelAnett SefrinCordula Giesler…
Physicians & Nurses Patients
Funding (big elephant in the room)Federal Ministry for Education & Research (BMBF) European Union FP7 and H2020 projectsGerman Council of Science and Humanities §91b
Acknowledgement
Patients